Antinflammatory salicyl morpholide



United States Patent 3,265,575 ANTIINFLAMMATORY SALICYL MORPHOLIDEAlfred Halpern, Great Neck, N.Y., assignor to Synergistics, Inc., NewYork, N.Y., a corporation of New York No Drawing. Filed Sept. 30, 1963,Ser. No. 324,595 20 Claims. (Cl. 167-65) The present invention relatesto the utilization of salicyl morpholide as an antiinflammatory agentand also to its use in combination with substances capable of exertingan antiinflammatory effect, as for example, corticoid steroids andbutazolidin, and antimitotic agents such as colchicine, in the therapyof humans.

This application is a continuation-in-part of applicants copendingapplication, Serial No. 174,358, filed February 14, 1962, and nowabandoned, which in turn was a continuation-in-part of applicationSerial No. 107,281, filed March 9, 1961, and now abandoned, which inturn was a continuation-in-part of application Serial No. 744,503, filedJune 25, 1958, which in turn was a continuation-inpart of applicationSerial No. 671,563, filed July 12, 1957, and now abandoned.

In response to stress, the activity of the adrenal cortex is greatlyincreased and this response is mediated through the anterior pituitarygland and more specifically, by the adrenocorticotropic hormone (ACTH).Although the exact mechanism by which discharge of ACTH is regulated,however, has not been completely established, we know that itsphysiologic and therapeutic effects depend upon the secretion ofcorticoid steroids. The adrenocorticotropic hormones of the anteriorpituitary gland and the steroids of the adrenal cortex as well as theirsynthetic derivatives are frequently considered together, since theireffects involve a common site of action. However, it should berecognized that the adrenocorticotropic hormone has a differentphysiology, chemistry, absorption and metabolism and, except for itsultimate therapeutic effect, is a unique and separate entity.

All known adrenal hormones are typical steroids resembling both theestrogenic and androgenic compounds in structure. Approximately 30 suchsteroid substances have now been isolated from the adrenal glands ofanimals and man, but only a few have any demonstrable activity. Thecorticoid steroids both naturally and synthetically derived, of presentmedical use as antiinflammatory agents are: desoxycorticosterone,cortisone, cortisone acetate, hydrocortisone, hydrocortisone-tert-butylacetate, hydrocortisone 21 B-cyclopentanepropionate,hydrocortisone-Zl-sodium succinate, prednisolone, prednisolone sodiumphosphate, prednisolone 21 acetate, prednisolone-tert-butyl acetate,prednisone, prednisone- 2l-acetate.

Hydrocortisone is believed to be the true adrenal glucocorticoid of man;cortisone being either a precursor or metabolite thereof. The morerecent synthetic modifications of hydrocortisone have the samequalitative pharmacologic properties, but show individual quantitativedifferences from the parent compound. Thus, the pharmacologictherapeutic use and side reactions of these compounds are essentiallythe same, but variations exist from compound to compound in connectionwith potency duration of activity and dosage required.

Patients with adrenal or pituitary suppression, or both, cannot toleratestress, as for example, surgery, trauma or infection. Thus, specialcaution in steroid therapy must be utilized if emergency surgery isnecessary and particular treatment is necessary during the immediatepost-operative phase, until functioning endogenous adrenal corticalactivity is restored. Even in minor surgical procedures, minor injuriesor minor infections, where little if any added hormonal protection isnecessary, the patient with a depressed level of adrenocortical3,265,575 Patented August 9, 1966 hormones may suddenly evidence shockor circulatory collapse. The administration of the corticoid steroidsinhibits the inflammatory process and during prolonged therapy infectionmay develop without previous signs and symptoms. Thus, the utmostcaution is necessary in order to initiate appropriate antibiotic andchemotherapeutic procedures before the infection proceeds touncontrollable limits.

In addition to'these generalized noxious properties of the overalleffect of continued administration of corticoid steroids, many seriousside-effects in their ordinary use have been observed and these pose aserious and special problem to the physician. Psychiatric changes may beinduced by the administration of these compounds, which range fromsimple euphoria to severe psychotic episodes. In children especially,convulsive seizures may occur, in fact, brain wave changes may occur inpractically all patients receiving these drugs whether or not clinicalabnormalities develop.

Disturbances in electrolyte metabolism involving sodium retention andpotassium loss are most frequently encountered. In certain individuals,as for example, those predisposed to congestive heart failure or inovert congestive heart failure, the retention of the sodium ion poses aserious threat to their continuing cardiac status. The concomitantpotassium loss may proceed to a hypokalemia, with consequent symptoms offatigue, muscular weakness and electrocardiographic changes.

An alteration in carbohydrate tolerance has been observed in somepatients who may develop glycosuria, fasting hyperglycemia and atendency for the glucose tolerance curve to approach that seen indiabetes. On an infrequent occasion, a patient will develop diabetesmellitus during corticoid steroid therapy but this is reversible whenthe therapy is stopped.

Induced hypercorticism alters tissue reaction to injury, infection andtoxemia. This modification of the tissue response may mask such cardinalsigns of infection as fever, increased erythrocyte sedimentation rateand the C-reactive protein level. Hypercorticism increasessusceptibility of individuals to infections.

In the course of conventional therapy with corticoid steroid substances,peptic ulceration may develop and prolonged hypercorticism may beaccompanied by the eventual development or aggravation of osteoporosis,with the subsequent predisposition to fractures. This latter pathologicstate is especially important to patients with rheumatoid arthritis andwomen in the postmenopausal state. Physiologic changes may also beexpressed in the form of acne and hirsutism as well as moon face andmenstrual disturbances. Thus, it will be recognized that while thesepotent compounds have resulted in much benefit, their use is fraughtwith serious limitations and the side reactions observed limit thetherapeutic benefits.

There remains a recognized need to counterbalance the therapeuticadvantages of this important class of compounds with the occurrence ofside effects, in order to make this mode of therapy available to thosechronically ill patients who need it most.

This need is of particular importance to patients wherein aninflammatory tissue response is the predominant factor. Among the manyattempts to modify the inherent limitations of the steroid group ofcompounds and to preserve the antiinflammatory activity, has been thesynthesis of new derivatives or partial replacement of the more potentagent with a less potent compound. Thus, phenylbutazone, asyntheticagent, without steroid or hormonal properties, has beenproposed as an antiinflammatory agent for use in the rheumatic patent.Its toxicity is virtually the same as the corticoid steroids it wasintended to replace.

Thus, it will be readily appreciated that the replaceby either the oralor parenteral route is both its insolubility in aqueous and physiologicfluids and the high incidence of local tissue irritation resulting afterits use.

Alkali metal salts of salicylic acid are water soluble but these posethe problem of the corrosive alkaline pH of these compounds, which isnot compatible with normal tissue physiology. Another problem whicharises after the utilization of the alkali metal salts of salicylic acidis the interference with mineral ion balance as a result of the largedosages of salicylate required.

While the use of organic salts of salicylic acid have been resorted toin order to circumvent the alkalinity of the inorganic salicylate salts,as well as the physiologic effects of the excess of metallic ions, thisapproach'has been found to be unsatisfactory. The acidity of the stomachsoon decomposes these labile compounds into their component parts.

We have found that salicyl morpholide possesses none of thesedisadvantages since it is not a salt of salicyclic acid and is stableover the entire pH range encountered physiologically in both the humanand animal. Salicyl morpholide is not broken into an amine or salicylmoiety in the gastrointestinal tract but passes through the mucosal wallas an intact molecule.

Salicyl morpholide is a well defined crystalline compound which analyzesin excellent agreement with its theoretical requirements. It has theempirical formula C H NO a melting point of 174176 C. and a solubilityat 20 C. in terms of grams per 100 cc. as follows: water, 0.41; ethanol,3.3 and ether, 0.22. The pH of a 1 saturated aqueous solution is pH 6.2.

Salicyl morpholide is stable under the ordinary conditions of storageand does not hydrolyze in the gastrointestinal tract. It is absorbedinto the blood stream as a single entity in contrast to salicylic acidsalts. When salicyl morpholide is administered orally it does not causelocal irritation to the gastrointestinal mucosa as do salicylic acidsalts and is of relatively low toxicity, thereby permitting aflexibility of dosage, to meet the requirements of clinical medicine.

Salicyl morpholide is obtained by causing a salicylic acyl halide(chloride or bromide) to react with an equimolar quantity of morpholinein an inert medium. The reaction is substantially instantaneous and thedesired compound is obtained by evaporating the inert solvent. The driedresidue is crystallized from methanol or ethanol to yield the desiredamount in a high state of purity.

A method of preparing this compound is to cause the reaction between analkyl or aryl ester of salicylic acid and morpholine in order to effectthe formation of the amide. This process has the advantage ofeliminating the gaseous hydrogen halides resulting from the reactionbetween an acyl halide and morpholine and may be carried out withoutcumbersome traps for noxious gases or the use of special equipment.

Another method of preparing salicyl morpholide is to react salicylicacid anhydryde with morpholine in an inert medium, containing adehydrating agent. This method of preparation is a preferred one. Thecompound obtained as a result of this procedure, is in a high degree ofpurity and compares in every respect to those obtained by the previousmethods.

It has been found that when salicyl morpholide is administered inanimals a demonstrable blood level of this agent appears in thecirculation within fifteen minutes after administration, althoughmaximum levels occur about one hour afterward. Pharmacologic evidence ofthese facts is established by the data reported in Table I, which wasobtained in the following manner: A group of six rabbits of mixed sexwere fed a slurry of salicyl morpholide and water by intragastricintubation. Blood samples were obtained from the marginal ear vein atperiodic intervals of 15 minutes, one-half hour, one hour, two hours,three hours, four hours, five hours, and twentyfour hours, and theconcentration of salicyl morpholide in the blood sample determined.

TABLE I.AVERAGE BLOOD LEVELS OF SALICYL MORPHOLIDE FOLLOWINGINTRAGASTRIC INTUBATION IN RABBITS Mg. percent of Time: salicylmorpholide 15 minutes 16.5

30 minutes 16.1

1 hour 17.4

2hours 14.3

Shours 6.5 24 hours 5.7

An excess of 16 mg. percent of salicyl morpholide was achieved withinfifteen minutes and a peak of 17.4 mg. occurred at sixty minutes, afterwhich time the concentration steadily decreased although a level ofapproximately one-third of the peak value was found at the end oftwenty-four hours.

It is important to note that in the course of these experiments, it wasdemonstrated that salicyl morpholide is not hydrolyzed within thegastrointestinal tract but is absorbed into the circulation as an intactmolecule and that it is not decomposed into its component parts in theblood stream. This resistance to hydrolysis is further demonstrated bythe absence of free salicylic acid ions in the blood stream after theadministration of even high doses of salicyl morpholide. Experimentalconfirmation of the lack of hydrolytic cleavage of salicyl morpholide inaqueous and physiologic fluids was obtained by a special study. It wasdetermined that no free salicylic acid was found in the blood of rabbitsafter the administration of salicyl morpholide by intragastricintubation. However, when a sample of the blood of these rabbits whowere fed salicyl morpholide was treated with 10 N potassium hydroxidesolution, and autoclaved at 15 lbs. pressure for one hour and 15minutes, cleavage of the com-pound was observed. It is obvious that suchdrastic chemical treatment is far in excess of what Would be encounteredin the living human and that under the ordinary physiologic conditions,salicyl morpholide is absorbed intact and does not decompose into itscomponent parts.

When salicyl morpholide is administered to a patient suffering from aninflammatory disease process, as for example, rheumatoid arthritis, orbursitis, or to those patients having an inflammatory tissue response,such as would be present after surgery or infection, a promptantiinflammatory action is observed. This antiinflammatory action isdemonstrated by the lowering of the C-reactive protein blood level, inaddition to other changes.

Thus, when the blood level of C-reactive protein was determined for agroup of 5 patients, whose principal complaint was bursitis orrheumatoid arthritis, it Was found to range from plus 2 to plus 4, whichvalue is an indication of the presence of tissue inflammation. [ForC-reactive protein determinations see, Selman, D., and Halpern, A.,Angiology, 7: 292, (1956).] Salicyl morpholide was then administered tothese patients at a dos-age level of from 40 to 60 grains per day, andthe C-reactive protein levels re-determined after 48 hours, 96 hours andone Week, of therapy. At the end of 48 hours of therapy, the C-reactiveprotein blood level had fallen to 0 lill one patient, to plus 2 in twopatients, with no change in the other two patients. At the end of 96hours, the C-reactive protein level test was negative in two patients,plus 1 in two patients, and plus 2 in one patient. A comparable controlgroup, who did not receive any medication, continued to maintain aC-reactive blood level of from plus two to plus four during the sameperiod. The results of this study establish that salicyl morpholide iscapable of exerting an anti-inflammatory reaction to a degree which issuitable for therapy.

In another study, salicyl morpholide was administered to patients withchronic, inflammatory disease in order to evaluate the anti-inflammatoryproperties of this compound. The group of patients studied consisted of30 patients; 12 males and 18 females of from 46 to 74 years of age, andpresented the following complaints: rheumatoid arthritis patients);bursitis (7 patients); myositis (5 patients); and scleroderma (3patients). The dose of the drug administered to these patients rangedfrom 40 to 60 grains per day. All previous medication was stopped exceptfor antibiotics, when indicated.v The overall duration of study was fromthree to four months of therapy.

A comparable group of patients receiving no therapy were used as acontrol. The results were evaluated as excellent, if there was a reliefof accompanying pain and a remission of the objective signs of thedisease; good, if there was partial relief of pain and minimal remissionof objective symptoms; and poor, if there were no changes observed whencompared to the control group.

Twenty-two patients manifested an excellent response while on salicylmorpholide therapy, reporting relief of pain and greater flexibility ofjoint motion (where this was previously limited) and also a diminutionof local edema. Four patients reported fair relief of pain, withpersisting restriction in limb motion and also no appreciable diminutionin local tissue sensitivity. Four patients showed no change to thedosage levels of salicyl morpholide administered.

There were no incidents of gastrointestinal distress, allergic reactionsor any other side effects observed during the period of therapy and theconclusion of the investigator was that a satisfactory anti-inflammatoryresponse was obtained after the administration of salicyl morpholide tothese patients.

Intermittent C-reactive protein blood level determinations were carriedout with the entire group of 30 patients described above, utilizing theoffice technique according to the standard method (for methods utilizedin C-reactive protein determinations see, Selman, D., and Halpern, A.,Angiology, 7: 292, [1956]). At the start of the study, one patient hadplus 4 C-reactive protein level; 15 patients had plus 3 C-reactiveprotein levels; 1 exhibited a plus 2 level; three patients had a plus 1and in one patient the test was negative. The C-reactive protein bloodlevel was determined during the period of therapy and this test wasutilized as an objective criterion of the effects of the drug. Alowering of the C-reactive protein level while the patient was on drugtherapy was considered a positive demonstration of an antiinflammatoryeffect. The C-reactive protein levels for the group were determinedafter one week of therapy and the following results Were obtained.

No. patients: C-reactive protein blood level 8 Plus 3 10 Plus 2 6 Plus 16 0 After two weeks of therapy the C-reactive protein level wasdetermined to be No. patients: C-reactive protein blood level 2 Plus 312 Plus 2 9 Plus 1 7 0 After one month of therapy, the C-reactiveprotein level ratios were within comparable limits.

No. patients: C-reactive protein blood level 2 Plus 3 10 Plus 2 10 Plus1 8 0 The effect of salicyl morpholide on the C-reactive protein valuesdetermined in the 30 patients with inflammatory disorders, wasstatistically analyzed for significance.

TABLE II.-RAW DATA FOR STATISTICAL ANALYSIS Number of Patients with TimeObserved CRP Level Test Interval Treatment Start None 1 3 7 15 1 Oneweek 40 gr. SA*/day G 6 10 8 O Two weeks. 40 gr. SA*/day 7 9 12 2 0 Oneor two 40 gr. SA*/day 8 10 10 2 0 months.

*Salicyl morpholide.

C-reactive protein serum level observations during therapy periods werecompared with results observed during the period of no therapy.Differences between serum levels without treatment and under treatmentwith salicyl morpholide generate chi-square values which quantify thelikelihood that these results could have occurred by chance andtherefore are indicative of the significance of the results. The detailsof the procedures used are described in: Cochran, W. G., and G. M. Cox,Experimental Design, pp. 100403, 407-411, John Wiley & Sons, New York,1950".

The probabilities for the comparison of the test results were found tobe as follows:

TABLE IlL-SUHMARIES OF THE SIGNIFICANCE OF TEST RESULTS OF THE EFFECT OFSALIGYL MORPHOLIDE ON C-REACTIVE PROTEIN FLUCTUATIONS These resultsestablish that the chi-square value for all treatment periods combinedwhen compared with the control periods exceeds the fractile value. Thiswould occur on the basis of chance only 5 times in 10,000 trials. Thisestablishes the view that salicyl morpholide produces changes in theserum levels of C-reactive proteins which would occur on the basis ofchance less than 5 times in 10,000 experimental trials which are highlystatistically significant changes. The changes in the serum C-reactiveprotein levels are also highly significant for individual treatmentperiods when compared with control. At the end of the second week theobserved changes in these serum levels would only occur by chance 5times in 1,000 experimental trials and at the end of one month, thechanges observed in these serum levels would occur by chance only 1 timein 1,000 trials. Only those changes in serum levels recorded in thefirst week generate chi-square values which have border-linesignificance at the 5% level.

In still another study, a group of ten patients presently receivinghydrocortisone therapy for rheumatoid arthritis and presently maintainedon the dosage schedule of from 20 to 30 mg. per day were studied for theeffects of salicyl morpholide as a partial replacement for this steroiddrug in their therapeutic regimen. The dosage of hydrocortisone wasreduced to 5 mg. per day and 40 grains per day of salicyl morpholide wasadministered concomitantly. The patients were observed at weeklyfollow-up visits and the effect of this therapeutic regimen evaluated.At the end of two weeks, six patients of the group of ten, weresatisfactorily maintained on this regimen, and in the remaining four,the dosage of salicyl morpholide was increased to 60 grains per day.After two weeks of treatment at the elevated dosage of salicylmorpholide, only one of this latter group of four patients appeared tobe satisfactorily maintained. The dosage of hydrocortisone was thenincreased to 10 mg. per day for these three patients and the amount ofsalicyl morpholide reduced to 40 grains per day. After two weeks oftherapy at this dosage level, the patients status appeared to indicatethat satisfactory maintenance regimens had been achieved in two patientsof this group and no benefit in one. This latter patient required areturn to the original maintenance dosage of 30 mg. per day.

Hence, it was observed that for six patients a replacement ofapproximately 75 percent to 80 percent of the daily hydrocortisonerequirements could be achieved by the substitution of 40 grains ofsalicyl morpholide per day. Three patients required 60 grains of salicylmorpholide to effect a reduction in hydrocortisone dosage of from 50 to75 percent of their previous daily maintenance requirement, and therewas no response in one patient. Thus, the anti-inflammatory propertiesof salicyl morpholide appear to be mediated through the adrenal glandand the effect of salicyll morpholide on the adrenal gland would appearto be to increase the endogenous hydrocortisone activity.

Statistical analysis was carried out again by standard chi-square testsfor which results of treatments of the 10 patients with rheumatoidarthrtis are classified according to the supportive level attained.

TABLE IV.RAW DATA FOR STATISTICAL ANALYSIS (b) 40 grains salicylmorpholide plus mg. hydrocortisone. (e) 60 grains salicyl morpholideplus 5 mg. hydrocortisone. (d) 40 grains salicyl morpholide plus mg.hydrocortisone.

A series of three analytical comparisons were made: (1) hydrocortisonevs. control; (2) combined therapy vs. control; (3) hydrocortisone vs.combined therapy.

TABLE V.RESULTS OF THE STATISTICAL ANALYSIS Comparison Chi-squaresProbabilities 16. 20 Less than 0.0005 (1 d.f.). 12. 93 Less than 0.0005(1 d.f.).

0. 85 Greater than 0.30 (1 d.f.).

Comparison 1Treatment with hydrocortisone, 20 mg. to 30 mg.-Thechi-square exceeds the fractile value, this would occur by chance only 5times in 10,000 experimental trials, indicating that the heavy dosage ofhydrocortisone for the patients with these inflammatory disordersproduces highly significant supportive effects related specifically tothe large dose levels of hydrocortisone used.

Comparison 2Treatment with varying doses of salicyl morpholide with asharply reduced intake of hydrocortisone.-The chi-square value againexceeds the fractile value which occurs by chance 5 times in 10,000trials, indicating that combined therapy of salicyl morpholide and alowered dosage of the steroid produce highly significant supportiveeffects related specifically to the employment of this combination ofthe drugs. This positive effect is obtained despite the drasticreduction in the amount of steroid dosage.

Comparison 3-C0mparis0n between tre atments.The chi-square value issmaller than the fractile value which occurs by chance 30% of the time,indicating that there is no detectable difference between the supportiveeffects '8 of combined therapy and that of heavy dosages ofhydrocortisone, upholding the view regarding the steroid-enhancingantiinfiammatory activity of salicyl morpholide.

A further advantage of salicyl morpholide for lOngterm use in thetreatment of patients with chronic inflammatory disease is its lack oflocal gastrointestinal irritation which permits a high dosage of thedrug to be ad ministered. There was no tolerance observed to continuedadministration of the drug and there was no interference with the acidbase balance of the blood after the administration of the large doses inthese studies.

In recent years pyrazolidone derivatives, namely3,5-diozo-l,2-diphenyl-4-n-butyl pyrazolidine, have been utilized in thetreatment of various arthralgic states, despite a number of inherentlimitations. The commonly accepted name for this substance isphenylbutazone. Phenylbutazone has been demonstrated to have a markedcapacity to raise the pain threshold in laboratory animals as well asexerting an antipyretic effect. Phenylbutazone exhibits antiinflammatoryproperties in animals similar to steroids, although it has been shownthat this action is not mediated through the pituitary-adrenal cortexaxis. Phenylbutazone causes sodium retention, which leads to edema.Tissue respiration studies have shown that oxygen consumption of braintissue is lowered during phenylbutazone therapy, as is the utilizationof glucose by the tissues. Phenylbutazone is slowly metabolized in man.The rate of bio-transformation varies with different subjects althoughthe range in biometabolism has been postulated to be from 10 percent to40 percent per day. The use of large doses of this drug, which isnecessary to achieve the therapeutic effect desired, has resulted inserious toxic manifestations. The use of the drug has been enjoined withcareful constant follow-up of the patients blood status, since severeblood dyscrasias have been reported after its use and liver damage hasalso been observed after its use. When salicyl morpholide isadministered concomitantly and simultaneously with phenylbutazone orpyrazolidone derivatives exerting a similar effect, either incombination as a single dosage form or by co-administration, theanti-inflammatory properties of salicyl morpholide permit the reductionin the dosage of phenylbutazone so that the noxious toxic effects may beavoided without modifying the therapeutic effects of the regimen. Thus,the full therapeutic spectrum of phenylbutazone may be obtained withoutthe occurrence of liver damage or blood dyscrasias, since theadministered dose may be greatly reduced. Thus, while the initial dailydosage ranges from 300 to 600 mg. of phenylbutazone, and a maintenancedosage of 100 to 200 mg. per day is utilized in therapy, this dosage maybe reduced from 50 percent to 75 percent by the addition of from 0.2 to3.2 gins. of salicyl morpholide per day, administered concornitantly.

Another drug which has been used with therapeutic benefit for the reliefof the symptomatology of inflammatory bone and tissue disease iscolchicine. Here we find that the drug, because of the quantitiesnecessary to exert a therapeutic effect, cause severe gastrointestinaldistress. However, when colchicine is combined with salicyl morpholidein the therapeutic regimen, the dosage of colchicine may be greatlylowered without impairing its therapeutic efficacy. A reduction in theeffective dosage of colchicine may range from 25 percent to percent whenadministered with 0.2 to 3.2 gm. of salicyl morpholide per day. Thus,the noxious gastrointestinal effects may be avoided and the drug whichis capable of exerting great benefit may now be administered to patientswho were formerly denied desirable pharmacologic effects because of theonset of local gastrointestinal irritation. This is of particularsignificance when it is recognized that colchicine is considered thedrug of choice in the treatment of gout and the unilateral arthridites,pathalogic states which are common and present a crippling phenomena toour aging population.

'is added one mol of phenyl salicylate.

9. Example 1 To one-tenth mol of salicylic acid in'a three-necked roundbottom boiling flask, fitted with a reflux condenser (attached to a gasabsorption trap), a mechanical stirrer and a delivery funnel, is addedtwo-tenths mol of thionyl chloride. The mixture is refluxed until nofurther evolution of hydrogen chloride occurs (approximately one-halfhour), and the excess thionyl chloride distilled. To the resultingsalicylic acyl chloride is added exactly one-tenth mol of morpholine,dissolved in 200 cc. of dry benzene. The reaction mixture is stirred atroom temperature for one hour and the benzene is slowly distilled over aperiod of one to one and one-half hours. The dry residue comprisingsalicyl morpholide is mixed with 250 cc. of 1 percent sodium bicarbonatesolution and warmed for fifteen to twenty minutes at a temperature ofabout 40 C., cooled and filtered. The insoluble material is dried andthen dissolved in just sufficient hot methanol to achieve solution andthe whole set aside to crystallize. On cooling overnight in anice-chart, crystals of salicyl morpholide, melting at 174-176 C. areobtained in a yield of better than eighty percent which analyzes forcarbon, hydrogen and nitrogen in excellent agreement with theoreticalvalues.

To three mols of morpholine in a round-bottom, boiling flask fitted witha reflux condenser and a stirring device, The mixture is heated toapproximately 130 C. and the stirring started. The reaction mixture ismaintained at this temperature for two hours and the excess morpholinedistilled under reduced pressure (2-3 mm. Hg). The residue is dissolvedin one liter of methanol with the aid of gentle heat and crystallizedovernight in an ice-box. Salicyl morpholide is obtained in better than90 percent yield and conforms in every respect with the product isolatedas a result of Example 1, above.

Example 3 To 0.5 mol of salicylic acid anhydride dissolved in one literof dry benzene is added 0.5 mol of morpholine dissolved in 500 cc. ofdry benzene. The mixture is warmed to reflux for two hours and thesolvent distilled. The residue is crystallized from hot methanol toyield salicyl morpholide, M.P. l74176 C. in better than 95 percentyield.

Example 4 Tablets or capsules for oral administration should be preparedto contain not less than 50 mg. and not more than 400 mg. of salicylmorpholide per unit dose. Because the active ingredient is relativelynot toxic, such tablets or capsules may be administered up to a totaldaily dosage of 5 grams, dependentupon the patients requirements.Preferably, it will be found that pharmaceutically desirable tablets andcapsules may be prepared to contain about 350 mg. of the therapeuticallyactive compound. Besides salicyl morpholide, the tablet may contain theusual carrier ingredients, as well as a disintegrating agent.

In preparing a tablet, it is first necessary to make up a carrier basegranulation containing powdered sucrose,

powdered lactose or powdered corn starch. If desired, the coloring agentmay be incorporated with the base granulation by either mixing it withthe dry powder or incorporating it into the granulating solution, whichconsists of either 5 percent gelatin, or 5 percent acacia solution. Thedried powder is uniformly moistened with this granulating solution andthen screened coarsely through No. 4 to No. 12 mesh screen, depending onthe properties of the dampened mass and then spread on trays, in thinlayers, to dry. granulation, then the temperature must not exceed 65 C.When dry, the mass is further sieved through a No. 16 or No. 20 screen.

The salicyl morpholide is then mixed with a lubricating agent, such ascalcium or magnesium stearate, and a disintegrating agent, as forexample, powdered corn starch, and the whole intimately mixed. Thesalicyl morpholide mixture is then added to the base granulation and themixture blended so as to form a uniform composition, which is thencompressed into tablet form. A typical formulation for tablets may be asfollows (all parts are by weight) 350 parts of salicyl morpholide partsof powdered lactose 3 parts of magnesium stearate 2 parts of powderedcorn starch For the preparation of capsules, the salicyl morpholide maybe filled directly into the appropriately shaped gelatin capsule of theproper size or it may be mixed with a diluent as, for example, powderedlactose, powdered sucrose or powdered starch, and then filled into thegelating capsules.

Example 6 Salicyl morpholide may be incorporated into a liquid dose formpharmaceutical preparation through the use of an appropriate non-toxicpharmaceutical carrier such as ethanol, glycerine, propylene glycol orpolyoxyethylene glycol, or combinations of these, or utilized as asuspension by dispersing the active material in an aqueous vehicle suchas water or sugar syrup with the aid of a dispersing. agent. Any of thepharmaceutically acceptable dispersing agents may be utilized to preparethese suspensions, as for example, the fatty acid esters of sorbitol, ortheir polyoxyethylene derivatives (these agents are known to commerce asSpans and Tweens); or the.

vegetable gums, as for example, acacia or tragacanth or lecithin. Whenthe fatty acid esters of sorbitol or their polyoxyethylene derivativesare utilized as the dispersing agent, the range in concentration ofthese agents will depend upon the quantity of salicyl morpholide to bedispersed and the volume used will be from 0.1 percent to 2 percent.When the vegetable gums are utilized to achieve dispersion of the activedrug, they range in concentration from 5 to 10 percent. A concentrationfrom 5 to 15 percent of lecithin will be adequate to disperse salicylmorpholide in an aqueous medium.

The range of concentration of salicyl morpholide in the liquidpreparation should be formulated so as to contain from 50 to 400milligrams per unit dose which may be administered several times daily.

In preparing a solution, the appropriate quantity of active material isdissolved with the aid of gentle heat in a pharmaceutically acceptablesolvent, as for example, ethanol, propylene glycol, glycerine, orpolyoxyethylene glycol. The solution is cooled and filtered. Appropriateflavoring and coloring agents may be added, if desired.

When an aqueous suspension is desired, the appropriate suspending ordispersing agent is mixed with. the salicyl morpholide and a smallquantity of the vehicle added to make a base dispersion. This is thendiluted under continuous agitation with additional quantities of thevehicle until the proper volumeis achieved. It may If heat is used todry the:

ll be found desirable to pass the entire suspension through any of theconventional homogenization apparatus for more uniform dispersion.

The solution and dispersions are stable and homogeneous and may beconveniently used in therapy.

Example 7 When it is desired to administer salicyl morpholide by therectal route, then the active ingredient may be incorporated in apharmaceutically acceptable suppository base, as for example, cocoabutter, polyoxyethylene glycol of a molecular weight from 1500 to 6000(compounds which are known in commerce as Carbowax), orglycerine-gelatine mixtures. Suppositories may be made with the aid ofconventional molding equipment and each suppository should contain arange in concentration of active therapeutic compound from 50 mg. to 400mg.

The appropriate quantity of salicyl morpholide is mixed with .theselected suppository base, utilizing the conventional techniques ofeither milling or dispersion in the molten base-composition. Thesuppositories are formed by filling the mold with the mixture by eithera hot pour or extrusion techniques.

By reason of the extraordinary stability and lack of dissociation intofree salicylic acid ions, salicyl morpholide permits the use of largequantities of analgetic agents without the occurrence of local tissueirritation.

Example 8 When it is desired to obtain an antiinflammatory effect, inanimals or humans, salicyl morpholide may be administered byintragastric intubation of a slurry of salicyl morpholide in water(concentration of active material, 20 percent, by weight) or by tablet,capsule, or liquid dose form, as for example, elixir, tincture, orsuspension or as a suppository for rectal administration. The range inconcentration of the active material when administered in either theoral or rectal routes is from 50 mg. to 400 mg. per unit dose. The totalquantity of the drug which may be administered to an individual patientper day, may be as high as grams.

Salicyl morpholide will be found in the blood stream within fifteenminutes after administration and will achieve a peak blood level withinone hour, after which time it will be eliminated via the normalmetabolic pathways. There are no free ions of salicylic acid observed inthe blood after the administration of salicyl morpholide, nor is therealteration of the acid-base balance of the blood after itsadministration even when high dosages are used. The compound may beadministered under chronic regimens and no occurrence of untowardnoxious side reactions which effect either the liver or the kidneys,have been observed.

Example 9 When it is desired to obtain an antiinflammatory effect in thepatient presenting a muscular-skeletal disorder, associated with localtissue or joint inflammatory disease, as for example, rheumatoidarthritis, bursitis or myositis, or to provide an antiinflammatoryeffect during the postoperative period, salicyl morpholide may beadministered by either the oral or rectal routes, utilizing the abovedescribed dose forms for a daily dosage level of from 0.5 gram to 5grams of the active therapeutic compound. An antiinflammatory effectwill be observed in the patient as evidenced by a greater degree ofjoint mobility, lessening of the pain, incidental to the reduction ofinflammation, and a reduction in the C-reactive protein level of theblood. Salicyl morpholide may be prescribed as tablets, capsules,teaspoonful or suppository dose-form, at a dosage range of from 100 mg.to 400 mg., to be taken one to eight times per day, depending upon thepatients need. The antiinflammatory properties of salicyl morpholidewill be observed after the administration of the drug in that anincreasing joint mobility as well as a decrease in local inflammation,will result.

12 Example 10 When it is desired to obtain an antiinflammatory effect inthe patients presenting those pathologic states requiring long-termadministration of conticoid steroids, as for example, such mesenchymaldiseases as rheumatoid arthritis, rheumatic fever, disseminated lupuserythematosus, periarteritis nodosa, dermatomyositis, scleroderma,bursitis, and calcific tendonitis or allergic diseases such as acute andchronic bronchial asthma, status asthmaticus, nasal polyps, acute drugreactions, contact dermatitis, and atopic dermatitis, or metabolicdiseases such as spontaneous hypoglycemia, or acute gouty arthritis, ordiseases of the skin, such as pemphigus, exfoliative dermatitis, drugeruptions, anaphylactoid purpura, chronic eczema, atopic dermatitis orgastrointestinal diseases such as sprue, ulcerative colitis, regionalileitis, and chronic hepatic disease or diseases of the eye, such asallergic conjunctivitis, vernal conjunctivitis, episcleritis, marginalulcer, uveitis, acute optic neuritis, chemical and thermal burns of theeye, or neoplastic disease, such as leukemia, lymphoma and carcinoma ofthe breast, of dental and oral diseases, such as rheumatoid arthritis ofthe temporomandibular joint and allergic stomatitis and glossitis, thena reduced maintenance regimen of the-corticoid steroids may beprescribed together with a supplementation dosage of salicyl morpholide.

When such a dosage regimen is utilized in therapy, the corticoid steroidis combined with the salicyl morpholide into a single dosage form. Thus,hydrocortisone may be combined with salicyl morpholide into a singletablet, capsule, suppository or liquid unit dose form or other dosageform, utilizing a ratio of from 1 to 5 mg. of hydrocortisone for each 50to 400 mg. of salicyl morpholide contained in the particular unit dosageform selected. The active ingredients are combined and added to thepharmaceutical carrier. The procedures described in Example 5 may beusedto prepare combination tablets and that of Example 7 to preparesuppository medication.

The daily dosage range of the combination of corticoid steroids andsalicyl morpholide will depend upon the individual patient, as well asthe potency of the corticoid steroid utilized. Thus, the daily dosagerequirement of hydrocortisone will be higher than that of prednisolonefor the same patient because of the variations in potency of these twocompounds. Similarly, the degree of severity of the disease within thepatient may require more or less of the corticoid steroid.

However, it will be found that a range of from 4 to 40 mg. ofhydrocortisone in combination with from 0.2 to 3.2 mg. of salicylmorpholide per day, will be adequate to treat the patients requiringthis form of medication. This same range in daily dosage requirementsapplies irrespective of whether tablets, capsules, suppositories orliquid dosage form is used. It is preferred that the total daily dose bedivided into from 3 to 8 portions, administered throughout the day inorder to maintain a uniform blood level.

Example 11 In place of the hydrocortisone used as described in Example10, above, there may be substituted any of the following corticoidsteroid compounds, in the particular ratios described below for eachrespective compound, to prepare unit dosage forms as described inExample 10, which comprises a combination of corticoid steroid compoundand salicyl morpholide:

Mg. Cortisone 1 to 5 Cortisone acetate l to 5 Hydrocortisone-tert-butylacetate 1 to 5 Hydrocortisone-Zzlfl-cyclopentanepropionate 1 to 5Hydrocor-tisone-Zl-sodium succinate 1 to 5 Prednisolone 0.1 to 3Prednisolone sodium phosphate 0.1 to 3 Prednisolone ZI-acetate 0.1 to 3Mg. Prednisolone-tert-butyl acetate 0.1 to 3 Predni'sone 0.1 to 3Prednisone-Zbacetate 0.1 to 3 When it is desired to utilize thesecombinations of this combined form of therapy, it will be found that thedaily dosage range for the combination of the corticoid steroidcompound, listed below, and salicyl morpholide, to treat patientsrequiring this form of medication, is:

Cr-tisoneFrom 4 mg. to 40 mg. of cortisone in combination with'from 0.2gm. to 3.2 gm. of salicyl morpholide.

Cortisone aceta-te--From 4 mg. to 40 mg. of cortisone in combinationwith from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Hydrocortisone-tert butyl acetate-From 4 mg. to 40 mg. of cortisone incombination with from 0. 2 gm. to 3.2 gm. of salicyl morpholide.

Hydrocortisone 21,8 cyclopentanepropionate From 4 mg. to 40 mg. ofcortisone in combination with from 0.2 gm. to 3.2 gm. of salicylmorpholide.

HydrocortisoneJrI-sodium succinateFrom 4 mg. to 40 mg. of cortisone incombination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

PId1liSOlOI1C-IFI'0II1 .4 mg. 'to 25 mg. per day, in combination withfrom 0.2 gm. to 3.2 gm. of salicyl morpholide.

Prednisolone sodium phosphate-4 mm .4 mg. to 25 mg., per day, incombination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Prednisolone 2 l-acetate-From .4 mg to 25 mg., per day, in combinationwith from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Prednisolone-tert-butyl acetateFrom .4 mg. to 25 mg, per day, incombination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Prednisone- From .4 mg. to 25 mg, per day, in combination with from 0.2gm. to 3.2 gm. of salicyl morpholide.

Prednis-one-Zl-acetateFrom .4 mg. to 25 mg, per day, in combination withfrom 0.2 gm. to 3.2 gm. of salicyl morpholide.

This same range in daily dosage requirements applies When either tables,capsules, suppositories or the liquid dosage form is used. It ispreferred that the total daily dose be divided into from 3 to 8portions, administered throughout the day in order to maintain a uniformblood level.

Example 12 When it is desired to obtain an antiinflammatory effect inpatient-s presenting those pathologic states requiring administration ofpyrazolidone derivatives such as 3,5-dix0 1,2 diphenyl 4 n butylpyrazolidine, which is commonly known as phenylbutazone, for the purposeof treating such disease manifestations such as rheumatoid arthritis,gouty arthritis, rheumatoid spondylitis, osteoarthritis, psoriaticarthritis, painful shoulder syndrome and acute superficialthrombophlebitis, then phenylbutazone in combination with salicylmorpholide may be administered by either the oral, rectal or parenteralroutes. The ratio of the combination of phenylbutazone and salicylmorpholide is from 50 to 300 mg. of phenylbutazone to 0.2 to 3.2 gm. ofsalicyl morpholide, administered in divided doses throughout the day.Thus, it may be desirable to utilize a tablet containing 50 mg. ofphenyl butazone and 400 mg. of salicyl morpholide, which would beadministered to the patient from 1 to 6 times daily, depending upon thepatients needs. The administration of such combination of medicationresults in a prompt remission of the acute symptomatology.

Should a liquid dosage form be desired, then a suitable elixir may beprepared utilizing from 20 percent to 40 percent of alcohol and theremainder of the vehicle being simple syrup. Suitable flavoring andcoloring may be added. The range of phenylbutazone may be from 50 mg. to300 mg., for each teaspoonful, although it will be found preferable toutilize the lower dosage of between 50 mg. and mg. per teaspoonful. Theconcentration of salicyl morpholide contained in this liquid preparationis from 200 mg. to 500 mg. per teaspoonful although it will be foundpreferable to utilize the lower range of from 200 mg. to 300 mg. perteaspoonful dose.

Similarly, when a suppository is desired, the conventional suppositorybase may be used and the range in phenylbutazone per unit suppository isfrom 50 mg. to 300 mg. and the concentration of salicyl morpholide perunit suppository is from 200 mg. to 500 mg.

Example 13 When it is desired to utilize a combination of colchicine andsalicyl morpholide in the treatment of the gouty arthridites or gout,then it may be administered in the form of a tablet, liquid orsuppository so that each unit dosage form contains from 0.2 to 0.5 mg.of colch-icine and 200 mg. to 500 mg. of salicyl morpholide. A promptreduction in symptomatology and degree of inflammatory disease present,will be observed soon after administration of this combination withoutthe onset of any of the local gastrointestinal distress usuallyaccompanying the administration of colchicine alone.

It is not desired to be limited except as set forth in the followingclaims, the above description 'being by way of illustration of theinvention.

What is claimed is:

1. A method of achieving an antiinflammatory effect in a human whichcomprises the step of the administration to such human of salicylmorpholide and a pharmaceutical carrier therefor.

2. A method of claim 1, said salicyl morpholide being administered inunit dosage form to such human containing from 50 to 400 mg. of saidcompound.

3. An antiinflammatory pharmaceutical preparation in unit dosage formcomprising salicyl morpholide and a corticoid steroid compound having anantiinflammatory efiect.

4. An antiinflammatory pharmaceutical preparation in unit dosage formcomprising from 50 to 400 mg. of salicyl morpholide and from 0.1 to 5mg. of a corticoid steroid compound having antiinflammatory effect and apharmaceutical carrier therefor.

5. An antiinflammatory pharmaceutical preparation in unit dosage form,comprising from 50 to 400 mg. of salicyl morpholide and from 1 to 5 mg.of hydrocortisone.

6. An antiinflammatory pharmaceutical preparation in unit dosage formcomprising from 50 to 400 mg. of salicyl morpholide and from 1 to 5 mg.of cortisone.

7. An antiinflammatory pharmaceutical preparation in unit dosage formcomprising from 50 to 400 mg. of salicyl morpholide and from 0.1 to 3mg. of prednisone.

8. An antiinflammatory pharmaceutical preparation in unit dosage formcomprising from 50 to 400 mg. of salicyl morpholide and from 0.1 to 3mg. of prednisolone.

9. An antiinflammatory pharmaceutical preparation in unit dosage formcomprising from 50 to 400 mg. of salicyl morpholide and from 50 to 300mg. of phenylbutazone.

10. An antiinflammatory pharmaceutical preparation in unit dosage formcomprising from 50 to 400 mg. of salicyl morpholide and from 0.2 to 0.5mg. of co'lchicine.

11. The method of obtaining an antiinflammatory effect in a humanpresenting a tissue inflammatory reaction which comprises the step ofthe administration to such human in unit dosage form of salicylmorpholide and a compound selected from the group consisting ofcorticoid steroids having an antiinflammatory effect, phenylbutazone andcolchicine.

12. The method of obtaining an antiinflammatory effect in a humanpresenting tissue inflammatory reaction whichcomprises the step of theadministration to such human in unit dosage form of from 50 mg. to 400mg. of salicyl morpholide and from 0.1 to mg. of a corticoid steroidhaving anti-inflammatory action.

13. The method of obtaining an antiinflammatory eflect in a humanpresenting tissue inflammatory reaction which comprises the step of theadministration to such human in unit dosage form of from 50 to 400 mg.of salicyl morpholide and from 50 to 300 mg. of phenylbutazone.

14. The method of obtaining an antiinflammatory effect in a humanpresenting tissue inflammatory reaction which comprises the step of theadministration to such human in unit dosage form of from 50 to 400 mg.of salicyi morpholide and from 0.2 to 0.5 mg. of colchic-ine.

15. The method of obtaining an antiinflammatory effect in a humanpresenting tissue inflammatory reaction which comprises the step of theadministration to such human in unit dosage form of from 50 to 400 mg.of saii-cyl morpholide and from 0.1 to 3 mg. of prednisone.

16. The method of obtaining an antiinflammatory effect in a humanpresenting tissue inflammator eaction which comprises the step of theadministration to such human in unit dosage form of from 50 to 400 mg.of salicyl morpholide and from 0.1 to 3 mg. of predn-isolone.

17. The method of obtaining an antiinflammatory effect in a. humanpresenting tissue inflammatory reaction which comprises the step of theadministration to such human in unit dosage form of from 50 to 400 mg.of

salicyl morpholide and from 0.1 to 3 mg. of prednisolone sodiumphosphate.

18. The method of obtaining an antiinflammatory eflect in the patientsufieringfrom rheumatoid arthritis, bursitis, myositis,thrombophlebitis, gouty arthritis, osteoarthritis and spondylitis, whichcomprises the step of the administration to such patient in unit dosageform of from to 400 mg. of salicyl morpholide and a compound selectedfrom the group consisting of hydrocortisone, cortisone,hydrocortone-Zl-sodium sucoinate, prednisone, prednisolone,prednisolone-t-butyl acetate, phenylbutazone and colchicine.

19. The method of obtaining an antiinflammatory effect in a patientsuffering from thrombop-hlebitis which comprises the step of theadministration to such patient in unit dosage form of from 50 to 400mg.of salicyl morpholide and 50 to 300 mg. of phenylbutazone.

20. The method of obtaining an antiinflammatory effect in a patientsuffering from gout and gouty arthritis which comprises the step of theadministration to such patient in unit dosage form of from 50 to 400 mg.of salicyi morpholide and 0.2 to 0.5 mg. of colchioine.

No references cited.

JULIAN S. LEVITT, Primary Examiner.

MARTIN J. COHEN, Assistant Examiner.

1. A METHOD OF ACHIEVING AN ANTIINFLAMMATORY EFFECT IN A HUMAN WHICHCOMPRISES THE STEP OF THE ADMINISTRATION TO SUCH HUMAN OF SALICYLMORPHOLIDE AND A PHARMACEUTICAL CARRIER THEREFOR.